Cyclophosphamide
Cyclophosphamide is a potent **antineoplastic** and **immunosuppressive** agent used widely in veterinary medicine for dogs and cats. * **Antineoplastic Use**: Employed in combination protocols for lymphomas, leukemias, carcinomas, and sarcomas. Low-dose metronomic (continuous) therapy is also utilized to prevent sarcoma recurrence. * **Immunosuppressive Use**: Used for severe immune-mediated diseases such as systemic lupus erythematosus (SLE), immune-mediated thrombocytopenia (ITP), immune-mediated hemolytic anemia (IMHA), and pemphigus. > **Clinical Pearl**: Cyclophosphamide is cell-cycle phase nonspecific. Because it is a prodrug requiring hepatic activation, it is not a vesicant and can be given safely via peripheral veins, unlike many other chemotherapy agents.
Mechanism: Cyclophosphamide is a prodrug that is metabolized in the liver by **cytochrome P450** enzymes into active metabolites, primarily **phosphoramide mustard** and **acrolein**. **Phosphoramide mustard** โ acts as an alkylating agent โ forms cross-links within and between DNA strands โ interferes with DNA replication and RNA transcription โ triggers apoptosis and cell death. **Acrolein** is a toxic byproduct that concentrates in the urinary bladder and is responsible for sterile hemorrhagic cystitis. The drug also profoundly suppresses B-cell and T-cell function, leading to its immunosuppressive effects.
Dosing by species
- Immunosuppressant (ITP or IMHA) ยท 50 mg/m2 PO every 2nd day ยท PO ยท q48h ยท Ongoing ยท Author prefers cyclosporine or chlorambucil in cats.
- To slow progression of FIP ยท 2-4 mg/kg PO four times a week ยท PO ยท 4 times/week ยท Ongoing
- Chemical shearing agent ยท Historical use ยท PO/IV ยท Single ยท Single ยท Historical use only.
- Neoplastic diseases ยท 200 mg/m2 (usually 1 gram per horse per dose) IV every 1-2 weeks ยท IV ยท q1-2 weeks ยท Protocol dependent ยท Consult veterinary oncologist.
- Antineoplastic (lymphoma) in rabbits ยท 50 mg/m2 PO daily for 3 days each week OR 100-200 mg/m2 IV every 7 days ยท PO/IV ยท Varies ยท Protocol dependent ยท Consider fully implantable vascular access device for IV.
- To inhibit local recurrence in dogs with incompletely resected soft tissue sarcomas ยท 10 mg/m2 PO once daily with piroxicam at 0.3 mg/kg PO once daily ยท PO ยท q24h ยท Continuous (metronomic) ยท If unacceptable adverse effects develop, increase interval to every other day.
- Antineoplastic ยท 50 mg/m2 PO 4 days/week OR 250 mg/m2 PO once every 3 weeks OR 100-300 mg/m2 IV weekly ยท PO/IV ยท Varies ยท Protocol dependent ยท Consult veterinary oncologist.
Routes of administration
Contraindications
- Prior anaphylactic reactions to the drug
- Severe pre-existing myelosuppression (leukopenia, thrombocytopenia)
- Active infections where immunosuppression may be dangerous
- No specific contraindications available in the monograph, but clinically contraindicated in patients with severe pre-existing myelosuppression or active haemorrhagic cystitis.
- Pre-existing severe myelosuppression
- Active haemorrhagic cystitis
Adverse effects
- Myelosuppression (leukopenia, thrombocytopenia, anemia)
- Gastroenterocolitis (anorexia, nausea, vomiting, diarrhea)
- Sterile hemorrhagic cystitis (induced by acrolein metabolite)
- Alopecia (especially in continuously growing coats like Poodles and Old English Sheepdogs)
- Pulmonary infiltrates and fibrosis
- Hyponatremia
- Secondary leukemia
- Myelosuppression (nadir usually 5-14 days post-therapy)
- Sterile haemorrhagic cystitis (caused by acrolein metabolite)
- Bladder fibrosis
- Transitional cell carcinoma (secondary to chronic cystitis)
- Vomiting
- Diarrhoea
- Hepatotoxicity
- Nephrotoxicity
Drug interactions
- Allopurinol ยท May increase the myelosuppression caused by cyclophosphamide
- Doxorubicin ยท Potentiation of cardiotoxicity may occur ยท major
- Chloramphenicol ยท May inhibit cyclophosphamide metabolism ยท moderate
- Phenobarbital ยท May increase the rate of metabolism to active metabolites, increasing toxicity risk
- Thiazide Diuretics ยท May increase the myelosuppression caused by cyclophosphamide ยท major
- Succinylcholine ยท Metabolism may be slowed, prolonging effects due to decreased pseudocholinesterases
- Digoxin ยท Absorption of orally administered digoxin may be decreased (may occur several days after dosing) ยท moderate
- Barbiturates ยท Increase cyclophosphamide toxicity due to increased rate of conversion to metabolites ยท major
- Phenothiazines ยท Reduce cyclophosphamide efficacy ยท moderate
- Ondansetron ยท Reduce cyclophosphamide efficacy ยท moderate
- Insulin ยท Insulin requirements are altered by concurrent cyclophosphamide ยท moderate
- cimetidine ยท Inhibits hepatic cytochrome P450 enzyme pathway, potentially altering the metabolism and increasing toxicity of chemotherapeutics. ยท major
Monitoring
- Efficacy (tumor response or remission of immune-mediated disease)
- Complete Blood Count (CBC) regularly for myelosuppression (nadir typically 7-14 days)
- Urinalysis regularly for signs of sterile hemorrhagic cystitis (hematuria)
- Uric acid levels (blood and urine)
- White Blood Cell (WBC) count (regular monitoring recommended due to myelosuppression)
- Urinalysis (monitor for haematuria indicating sterile haemorrhagic cystitis)
- Renal and hepatic function panels
- Free-catch urine by dipstick prior to and each week of treatment
- Haematology
- Biochemistry (prior to first treatment and minimum every 6 months)
Overdose
Limited information on acute overdoses. The lethal dose in dogs is reported as **40 mg/kg IV**. If an oral overdose occurs, perform gut emptying (emesis/lavage) if indicated and hospitalize the animal for aggressive supportive care, including IV fluids to flush the bladder and prevent hemorrhagic cystitis.
VetSheet drug reference is intended for licensed veterinary professionals as a clinical decision-support aid, not a substitute for professional judgement or the manufacturerโs current label.